This is a multi-investigator, collaborative proposal based on the concept that respiratory epithelial stem/progenitor cell proliferation and differentiation are controlled, at least in part, by transcriptional mechanisms that determine gene expression, cell fates, and functions. Cellular replacement for therapy of severe pulmonary disorders will require detailed knowledge of the transcriptional programs that govern respiratory epithelial specification and differentiation. The long-term goals of this application are to 1) identify respiratory epithelial progenitor cells (REPCs) and the transcriptional programs mediating their proliferation and differentiation, and 2) assess the ability of these transcriptional mediators to engineer/program both endogenous respiratory epithelial progenitor cells and exogenous cells (including embryonic stem cells (ES) and multipotent stem cell progenitors (MSC/Ps), to exhibit respiratory epithelial differentiation that may be useful for cell replacement for life-threatening pulmonary disease. We will use mouse cells and transgenic mouse models to identify REPCs and the transcriptional programs regulating their proliferation and differentiation, seeking to identify subsets of conducting and peripheral airway cells that exhibit stem cell/progenitor cell behavior during lung regeneration/repair. Transcriptional engineering will be used to determine the scope of cellular plasticity and proliferation of REPCs, MSC/Ps, and ES cells. The ability of non-pulmonary cells to be transcriptionally engineered to express respiratory epithelial cell selective genes and functions will be determined. The experiments are designed to test the ability of both endogenous and exogenous REPCs to engraft in the lung and to contribute to repair of the respiratory epithelium. Clinically relevant mouse models will be utilized to assess this potential, with particular focus to post-pneumonectomy lung regeneration and repair after respiratory epithelial cell specific cell ablation and Sftpc-/- mice, the latter developing severe interstitial lung disease that is similar to that seen in individuals inheriting mutations in SFTPC, a gene causing idiopathic pulmonary fibrosis (IPF) in patients. A Stem Cell Consortium will be established at CCHMC, Univ. of Cincinnati College of Medicine to develop education, training, and research bridging hematopoietic stem cell and pulmonary stem cell biology on our campus.